Elucidating the role of class I HDACs in cardiac ischemia reperfusion injury

Medical University Of South Carolina, Charleston SC

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Abstract

? DESCRIPTION (provided by applicant): The overall goal of this proposal is to determine the effect of class I HDAC mediated changes in mitochondrial acetylation on mitochondrial function and mitochondrial transition pore (mPTP) opening in response to ischemia reperfusion (IR) injury in the heart. Although rapid reperfusion of ischemic tissue is the treatment of choice for myocardial infarction, much of the resultant damage to the heart occurs as a result of reperfusion itself. Previously, we have shown that pretreatment with MS-275, a selective class I histone deacetylase (HDAC) inhibitor, rescues left ventricular (LV) function and substantially reduces the area of infarcted tissue in isolated rat hearts in response to IR injury. Further, we found the effect of selective class I HDAC inhibition to be more protective than pan-HDAC inhibition with trichostatin A. We have also found that class I HDAC inhibition (MS-275) administered at reperfusion improves post-ischemic LV contractile function and preserves viable myocardium. Mass spectrometry analysis revealed that inhibition of class I HDACs changed the acetylation state of 16 mitochondrial proteins, including 3-ketoacyl CoA Thiolase, the last enzyme of beta oxidation, which may modulate mitochondrial permeability transition. We hypothesize that acetylation of 3-ketoacyl CoA thiolase preserves mitochondrial integrity in response to IR injury by preventing mPTP opening. To test this hypothesis, two aims are proposed. In Specific Aim 1 we will determine the mechanism by which class I HDACs modulate mitochondrial acetylation. In Specific Aim 2 we will determine the effect of 3-ketoacyl CoA thiolase acetylation on multiple parameters of mitochondrial function and the myocardial response to I/R injury ex vivo using a Langendorff perfusion apparatus. Results from these proposed studies will further our knowledge of the effects of changing acetylation profiles in ischemia reperfusion injury and shed light on a possible role of HDAC inhibitors in the treatment of acute myocardial infarction at the time of percutaneous coronary intervention.